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Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes
Sleep Medicine 34 (2017) 7e12
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Original Article
Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes b, Son a Nevsímalova b, Martin Matoulek a, Vladimír Tuka a, Magdalena Fialova b, * Karel Sonka a Centre of Cardiovascular Rehabilitation, Third Department of Medicine e Department of Endocrinology and Metabolism of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic b Department of Neurology and Centre of Clinical Neurosciences of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 December 2015 Received in revised form 17 November 2016 Accepted 16 February 2017 Available online 11 March 2017
Objective: Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. Patients and methods: The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. Results: In narcolepsy patients, maximal oxygen uptake (VO2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p ¼ 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO2peak%) and to a standard deviation (VO2peakSD) of 1.08 ± 1.63 mL/kg/min of the population norm. VO2peak depended primarily on gender (p ¼ 0.007) and on sleepiness (p ¼ 0.046). VO2peak% depended on sleepiness (p ¼ 0.028) and on age (p ¼ 0.039). VO2peakSD depended on the number of cataplexy episodes per month (p ¼ 0.015) and on age (p ¼ 0.030). Conclusions: Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency. © 2017 Elsevier B.V. All rights reserved.
Keywords: Exercise stress test Cardiopulmonary fitness Narcolepsy with cataplexy Narcolepsy without cataplexy Influence of disease severity
1. Introduction Narcolepsy is a chronic neurological disease that is characterized by excessive daytime sleepiness and is divided into narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwoC), due to differing etiologies [1]. NC occurs due to the loss of hypocretin (orexin) neurons in the lateral hypothalamus [2]. In addition to sleep and wakefulness regulation, hypocretin plays an important role in food intake regulation and metabolism. The etiology of NwoC is not well understood, and NwoC is not characterized by hypocretin deficiency in the cerebrospinal fluid.
* Corresponding author. Department of Neurology, First Faculty of Medicine, 30, Prague 2, 128 08, Charles University and General University Hospital, Katerinska Czech Republic. Fax: þ420 224 922 678. E-mail address: [email protected] (K. Sonka). http://dx.doi.org/10.1016/j.sleep.2017.02.017 1389-9457/© 2017 Elsevier B.V. All rights reserved.
Patients with narcolepsy have a lower quality of life compared to other neurological patients. On the Short Form36 questionnaire, the dimensions “physical functioning,” “vitality,” and “general health perception” have been found to be the main domains of health-related decreased quality of life [3]. Exercise tolerance is the strongest prognostic marker of all-cause mortality in the general population [4] and in different chronic diseases, for example, obesity, coronary artery disease, heart failure, and cancer [5]. Exercise tolerance depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy are reported to need more sleep during the daytime and are more fatigued than controls [6]; thus we may speculate that the main determinants of cardiopulmonary fitness in NC and NwoC are due to sleepiness and potentially to cataplexy episodes preventing patients from engaging in regular physical activity. The aim of the present study was to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness.
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2. Methods 2.1. Study population A total of 56 patients aged 18e65 years diagnosed with NC and NwoC, who were indicated for an exercise stress test before the initiation of an exercise program, were included in the present study (years 2013e2015). The age- and gender-matched control group was recruited from among participants of a preventive program for the general population to whom an exercise stress test was offered. All patients gave informed consent to participation in the study. The study was approved by the local ethical committee VFN), and was conducted in accordance with the (40/11 IGA MZCR Declaration of Helsinki. Of the 56 subjects who agreed to participate in the study, 42 patients completed the cardiopulmonary exercise stress test (CPX). One patient had difficulty breathing through the mouthpiece and did not want to reschedule the test with a mask. Thirteen patients did not attend the scheduled CPX and thus were not included. Of the 42 patients who completed the study, eight patients (19%) reported engaging in recreational sports. Five patients had arterial hypertension on monopharmacotherapy. One patient in the study population was treated with a b-blocker, another patient was treated with a statin, and two other patients were treated with a calcium channel blocker. Sixteen patients (38%) were current smokers and four patients (10%) were former smokers. There were no other diagnoses that could potentially affect the results of the CPX. Characteristics of the study population are summarized in Table 1, and the tests performed at narcolepsy diagnosis are summarized in Table 2. All patients were previously diagnosed at our institution, and only those patients with an unambiguous diagnosis were invited to participate. All patients were diagnosed according to the International Sleep Disorders Classification, second edition [1]. In all patients, night polysomnography (8 h) and the 5-nap multiple sleep latency test (MSLT) were performed without any concurrent treatment that could influence sleep or cataplexy. Polysomnography was performed according to the American Academy of Sleep Medicine (AASM) manual for the scoring of sleep and associated events [7] and the MSLT according to AASM rules [8]. Results concerning sleep-related breathing disorders and periodic limb movements in sleep (PLMS) were retrieved from the diagnostic night polysomnography data to provide information about other sleep disturbances. Obstructive sleep apnea (OSA) was diagnosed according to polysomnography (PSG) criteria (apnea/ hypopnea index 5). None of the patients fulfilled the diagnostic criteria for central sleep apnea [1]. Subjects were considered to have PLMS when the number of period leg movements per 1 h was 15 [7]. The mean latency between polysomnography and MSLT and the exercise stress test was 3.6 ± 4 years; however, information about general health status and pharmacological treatment was obtained at the date of the examination. The following information
was selected and processed from the clinical records of all patients: age at data collection, age at symptom onset, body height and weight, Epworth Sleepiness Scale (ESS) score [9], cataplexy episode frequency per month (subjectively assessed), sleep latency during MSLT, sleep efficacy during night polysomnography, rapid eye movement (REM) sleep latency during polysomnography, percentage of slow-wave sleep during night polysomnography, and percentage of REM sleep during night polysomnography. Treatment with stimulants (modafinil and methylphenidate), antidepressants (selective serotonin reuptake inhibitors, venlafaxine, clomipramine, and tianeptine) and sodium oxybate at the time of the exercise test was as summarized in Table 2. 2.2. Cardiopulmonary exercise stress test The CPX were carried out on a cycle ergometer (Ergoline e-Bike, GE Medical Systems, Milwaukee, WI, USA) at the same time, in the early afternoon. The work rate was corrected for body weight. We used a combined protocol with two consecutive 3-min steps, followed by a ramped increase in work intensity. The intensity of the first step was set to correspond to 0.5 Watt/kg (ie, 2.3 metabolic equivalents [METs]), increasing to 1.0 Watt/kg (ie, 4.7 METs) during the second step. Thereafter, a ramped increase in work intensity followed, consisting of 5 Watts/10 s, ie, 30 Watts/min, irrespective of body weight. Blood pressure (BP) measurements were performed by an experienced nurse at the beginning of the third minute of each workload, and at each odd minute during the ramped increase. BP was measured manually by a standard sphygmomanometer using the auscultatory method. Systolic BP (SBP) was recorded at the appearance of the Korotkoff phase I sound, and diastolic BP (DBP) at the disappearance or muffling of the Korotkoff sounds (phase IV or V); preference was at the complete disappearance of the Korotkoff sound, and in the case of uncertainty, diastolic pressure was not noted. Heart rate (HR) in beats per minute (bpm) was measured from the electrocardiogram (ECG) recording by Cardiosoft v6.51 (GE Medical Systems, Milwaukee, WI, USA). Analysis of expired gas was performed breath-by-breath using a Vmax Spectra 29s Cardiopulmonary Exercise Testing Instrument (SensorMedics Corporation, Yorba Linda, Canada). Flow and sensor calibration was performed before each test according to the device manual. The respiratory exchange ratio (RER; VCO2/VO2) and metabolic equivalent of tasks (METs; VO2/basal oxygen demand [3.5 mL/kg/min]) were calculated from the measured variables. Markers of cardiopulmonary fitness included VO2peak (mean from the last 30 s of the exercise test), expressed in mL/kg/min, as a percentage of the national norm (VO2peak%), as well as the number of standard deviations (SD) from the national norm (VO2peakSD). These data were derived from the specific national data from the International Biological Program [10], as it is widely used in reporting fitness data, in which less than 85% and less than one SD are considered abnormal [11].
Table 1 Characteristics of study population.
No. Age (y) Gender (male/female) Weight (kg) Height (cm) BMI
All narcolepsy
NC
NwoC
Control
42 34.9 ± 10.0 16/26 88.0 ± 53.0 171.8 ± 9.1 29.9 ± 5.7
32 35.0 ± 10.0 12/20 89.5 ± 15.3 171.4 ± 9.6 30.6 ± 5.6
10 34.6 ± 10.6 4/6 83.4 ± 20.9 173.0 ± 8.0 27.6 ± 5.7
36 35.3 ± 10.2 15/21 85.6 ± 20.3 174.3 ± 9.7 28.1 ± 6.2
BMI, body mass index; NC, narcolepsy patients; NwoC, narcolepsy patients without cataplexy.
Control vs all narcolepsy
NC vs NwoC
NS NS NS NS NS
NS NS NS NS NS
M. Matoulek et al. / Sleep Medicine 34 (2017) 7e12
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Table 2 Characteristics of patients with narcolepsy.
No. Age at disease onset (y) Duration of the disease (y) HLA DQB1*06:02 positivity/total number of subjects with available HLA typing Cataplexy (No./month) No. on stimulants No. on modafinil Mean dose of modafinil (mg) No. on methylphenidate Doses of methylphenidate (mg) No. on antidepressants No. on sodium oxybate Doses of oxybate (g) ESS MSLT, sleep latency (min) MSLT, No. of SOREMp PSG, sleep latency (min) PSG, sleep efficiency (%) PSG REM, sleep latency (min) PSG, REM duration (%) PSG, N3 duration (%) No. of patients diagnosed with OSA AHI No. of patients diagnosed with PLMS PLMI
All
NC
NwoC
NC vs NwoC
42 19.1 ± 9.0 15.3 ± 10.1 30/39
32 18.3 ± 7.8 16.0 ± 10.1 26/29
10 21.7 ± 12.2 13.1 ± 10.2 4/10
NS NS
9.2 ± 17.0 34 (81%) 30 (71%) 208 ± 66 4 (10%)
12.0 ± 18.7 26 (81%) 23 (72%) 209 ± 72 3 (10%) 10 mg; 10 mg; 40 mg 15 (47%) 5 (16%) 5 g, 5 g, 6 g, 6 g, 9 g 17.5 ± 3.6 2.4 ± 2.1 3.7 ± 1.1 7.3 ± 10.0 84.8 ± 8.9 31.9 ± 44.9 19.6 ± 6.0 18.4 ± 6.6 6 (19%) 6.5 ± 12.3 11 (34%) 15.4 ± 23.2
0±0 8 (80%) 7 (70%) 207 ± 42 1 (10%) 10 mg 1 (10%) 0 0 15.9 ± 4.5 3.3 ± 1.3 3.2 ± 0.9 8.0 ± 4.5 90.9 ± 4.9 68.2 ± 33.7 21.2 ± 4.5 17.6 ± 7.4 0 2.0 ± 0.9 2 (20%) 13.6 ± 21.7
16 (38%) 5 (12%) 17.1 ± 3.8 2.62 ± 1.93 3.5 ± 1.0 7.4 ± 9.2 86.3 ± 8.5 39.0 ± 44.9 19.9 ± 5.7 18.2 ± 6.6 6 (14%) 5.6 ± 11.1 13 (31%) 15.0 ± 22.6
NS NS NS NS
NS NS NS NS NS NS NS NS NS
AHI, apnea/hypopnea index; ESS, Epworth Sleepiness Scale; HLA, human leukocyte antigen; MSLT, multiple sleep latency test; NC, narcolepsy patients; NwoC, narcolepsy patients without cataplexy; No., number; OSA, obstructive sleep apnea; PLMI, periodic leg movements index (number of periodic leg movements per 1 h of sleep); PLMS, periodic limb movements in sleep; PSG, polysomnography; REM, rapid eye movement; SOREMp, sleep onset REM period.
2.3. Accelerometer use
3.1. Cardiopulmonary exercise stress test
We used an Omron Walking style Pro accelerometer (Omron Healthcare Europe, Hoofddorp, Netherlands) for step count, which has a measurement deviation of ±5%. The patients wore the accelerometers two weeks before CPX to document their usual physical activity. A direct estimate of minimal amounts of moderate-to-vigorous physical activity accumulated in the course of objectively monitored free-living behavior corresponds to 7000e8000 steps per day [12].
Data from the CPX are reported in Table 3. VO2peak was lower in narcoleptic patients than in controls (30.1 ± 7.5 mL/kg/min vs 36.0 ± 7.8 mL/kg/min; p ¼ 0.001), which corresponds to 86.4% ± 20.0% (vs 101.3% ± 15.4% in controls; p ¼ 0.0007) of the Czech population norm (VO2peak%) or a standard deviation (VO2peakSD) of 1.08 ± 1.63 mL/kg/min (vs 0.12 ± 1.27 mL/kg/min in controls; p ¼ 0.007) from the Czech population norm. The narcoleptic patients also achieved statistically nonsignificantly lower peak workloads than control subjects (223 ± 56 Watt vs 246 ± 69 Watt; p ¼ 0.099). The only statistically significant difference between NC and NwoC was HR at a work intensity of 0.5 Watt/ kg (114 ± 13 bpm vs 103 ± 16 bpm, p ¼ 0.037). Compared to NwoC patients, NC patients had lower values of VO2peak% (84.3% ± 18.9% vs 94.9% ± 22.1%; p ¼ 0.227) and VO2peakSD (1.26 ± 1.58 vs 0.37 ± 1.6 mL/kg/min; p ¼ 0.143), although the difference was not significant.
2.4. Statistical analysis All calculations were performed in SPSS v13.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± SD, and range was reported where appropriate. Comparison between the narcolepsy and control groups was performed with the Student t test. Comparison between the NC and NwoC groups was performed with the nonparametric ManneWhitney test. The Spearman correlation coefficient was used in evaluation between independent and dependent variables. Peak work rate indexed by body weight, VO2peak, and VO2peak% were chosen as dependent variables a priori. Linear regression with multivariate models was then applied with stepwise variable selection. The level of significance was set at p < 0.05. 3. Results Treatment for sleepiness and cataplexy at the time of the exercise stress test is outlined in Table 2. We collected data on the number of daily steps from 34 patients (26 NC and eight NwoC). The mean number of steps per day was 6346 ± 2026 in all patients, 6533 ± 1988 in NC, and 5739 ± 2163 NwoC (difference nonsignificant).
3.2. Linear regression analysis Spearman correlation coefficients were calculated to select appropriate independent variables for the stepwise linear regression analysis; the results of the analysis are summarized separately for NC and NwoC in Table 4 of the Supplementary materials. The number of cataplexy episodes per month, polysomnography-sleep efficiency, gender (male ¼ 1, female ¼ 2), age, body mass index (BMI), and resting HR were chosen as independent variables. The linear regression analysis showed that VO2peak depended primarily on gender (p ¼ 0.007) and on ESS (p ¼ 0.046). The regression equation for VO2peak was as follows:
VO2peak ¼51;7757;244Gender0;606ESS ½Gender : Male ¼ 1;Female ¼ 2
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Table 3 Cardiopulmonary exercise stress test data.
Narcolepsy group
Control group
SBP (mm Hg) DBP (mm Hg) HR (bpm) VO2 (mL/kg/min) SBP (mm Hg) DBP (mm Hg) HR (bpm) VO2 (mL/kg/min)
Rest
0.5 W/kg
1.0 W/kg
Peak
3-min Recovery
123 ± 15 80 ± 9 89 ± 14 N/A 127 ± 17 80 ± 10 89 ± 17 N/A
130 ± 17 81 ± 10 111 ± 15 12.3 ± 1.4 138 ± 22* 81 ± 10 110 ± 12 12.6 ± 1.1
152 ± 23 85 ± 10 134 ± 17 18.9 ± 1.7 157 ± 28 84 ± 10 132 ± 14 20.2 ± 1.5
173 ± 26 91 ± 16 176 ± 13 30.1 ± 7.5 183 ± 32 92 ± 10 175 ± 16 36.0 ± 7.8**
139 ± 20 74 ± 10 121 ± 16 N/A 146 ± 22 75 ± 11 124 ± 13 N/A
DBP, diastolic blood pressure; HR, heart rate; METs, metabolic equivalent of task; N/A, not applicable; RER, respiratory exchange ratio; RPE, rating of perceived exertion according to Borg; SBP, systolic blood pressure; VO2, oxygen consumption. *p < 0.05; **p < 0.01; ***p < 0.001.
VO2peak% depended on ESS (p ¼ 0.028) and on age (p ¼ 0.039). The regression equation for VO2peak% was as follows:
VO2peak % ¼ 89; 747 1; 813 ESS þ 0; 760 age: VO2peakSD depended on the number of cataplexy episodes per month (CAT) (p ¼ 0.015) and on age (p ¼ 0.030). The regression equation for VO2peakSD was as follows:
VO2peak SD ¼ 2; 993 0; 034 CAT þ 0; 063 age: 3.3. Differences between NC and NwoC The NC and NwoC groups differed only in SBP before the CPX (125 ± 15 mm Hg vs 113 ± 14 mm Hg, p ¼ 0.032) and HR during the first exercise stage corresponding to light exercise of 0.5 Watt/kg (114 ± 13 bpm vs 103 ± 16 bpm; p ¼ 0.037). No other significant differences between the two groups were detected. 4. Discussion This is the first study to provide data on cardiopulmonary fitness in patients with narcolepsy. The main findings of the present study are as follows: (1) cardiopulmonary fitness is inversely related to the degree of sleepiness in NC and NwoC and to the number of cataplexy attacks per month in NC; (2) patients with narcolepsy have lower cardiopulmonary fitness compared to the general population; and (3) with increasing age, cardiopulmonary fitness in narcolepsy patients approaches that of general population. 4.1. Lower cardiopulmonary fitness The training effect of exercise is dose dependent; less opportunity to be physically active (including physical activity such as walking, household work, etc) results in lower muscle recruitment and thus through a lower training effect to lower exercise tolerance [13]. In our study population, sleepiness was one of the variables that determined cardiopulmonary fitness. There are several explanations for a lower opportunity to perform physical exercise and to participate in leisure activities combined with sports, including time constraints due to sleepiness, social isolation, and BMI. All of these potential explanations may be applied not only on generally to lower cardiopulmonary fitness in NC and NwoC but also have a negative correlation with the intensity of sleepiness and the frequency of cataplexy episodes. Patients with NC and NwoC sleep more than controls during the daytime, especially during lower sleep-propensity zones (morning and late afternoon) [14], and the majority of patients with narcolepsy experience severe fatigue, which is different from daytime
sleepiness and which results in severe functional impairment [6]. This is in agreement with the model of orexin knock-out (KO) mice that have less spontaneous activity compared to wild-type mice [15]. Similarly, patients with narcolepsy experience more social isolation, as they fear falling asleep or having cataplexy episodes during moments of excitement. This also affects common collective leisure time activities, including sports. Anxiety and depression are frequent comorbidities in narcolepsy [16]. Anxiety and depression as well as health-related stigmata contribute to social isolation [17] and thus to nonparticipation in leisure time physical activity. There is evidence that patients do have limited participation in sport activities. Broughton et al. reported that patients with narcolepsy reported more problems in performing recreational and leisure-time activities compared to controls [18]. Daniels et al. found that 39.7% of British adult narcoleptics reported difficulties with playing sports due to narcolepsy [19]. In addition, Texeira et al. reported that 48% of patients with narcolepsy complained about difficulties playing sports [20]. The explanation of lower cardiopulmonary fitness by reduced daily physical activity in narcolepsy is supported by our data, showing a low average number of steps performed per day. These are below the minimal normative data from objectively monitored, free-living behavioral step count [12]. Similarly, reduced spontaneous activity in narcolepsy, even with modafinil treatment, has been recorded by actigraphy [21]. NC is due to a hypocretin (orexin) deficit [2]. In addition to sleep and wakefulness regulation, hypocretin plays an important role in food intake regulation and metabolism. Compared to healthy controls and NwoC patients, patients with NC have higher BMI, and the proportion of patients with obesity is higher in NC than in NwoC patients [22]. Chabas et al. reported that NC patients had a lower basal metabolism than controls and, surprisingly, that overweight patients ate half as much as others [23]. The behavioral explanations of lower cardiopulmonary fitness are in accordance with the murine orexin KO model. The contribution of orexin signaling to physical activity has been demonstrated in rodents [24]. The orexin KO mice initiated running as often as wild-type mice and ran at normal speed. Nevertheless, the total amount of running was 42% less, with shorter bouts. Of the running bouts, 35% were succeeded by cataplexy episodes or a quick transition to sleep. Orexin KO mice have short sleep latencies and rapid transitions to cataplexy episodes after running, which suggests that sleepiness and imminent cataplexy episodes may contribute behaviorally to their short running bouts and lower amount of time spent running during the day [25]. We observed increased sleepiness in our NC and NwoC patients, and they also took approximately 35% fewer steps per day than the 10,000 steps that a healthy nonsedentary adult takes [12]. These factors suggest a similar pathophysiological role of orexin deficiency in the murine model as well as in humans.
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4.2. Effect of age Narcolepsy is a chronic, lifelong disease that is believed to have a stable course; however, longitudinal studies are scarce [26]. It seems that NC is not a stable phenotype, especially in children, displaying characteristic evolution with an abrupt onset followed by partial improvement over time [27]. The onset of the disease is usually marked by weight gain, especially in childhood [28]. Older patients perceive the symptoms of narcolepsy as milder compared to their younger age [29]. Quality of life in narcolepsy patients also improves with the duration of symptoms [3,26,30], especially vitality [31]. This age-related improvement in narcolepsy symptoms has also been documented by a progressive decrease in the number of SOREMp with age and a progressive increase in mean sleep latency on the MSLT as a function of age [32]. Both the symptoms of the disease, which may reduce habitual physical activity, and the metabolic disturbances associated with narcolepsy are greater at the beginning of the disease and thus affect younger patients more. Cardiopulmonary fitness declines with age [12]; thus otherwise healthy senior patients with narcolepsy are closer to their age-matched counterparts, where the difference in cardiopulmonary fitness is not so pronounced as in younger patients. Narcolepsy is associated with increased morbidity and a trend toward higher mortality. Data from an extensive Danish National Patient Registry show that patients with narcolepsy have a higher prevalence of diabetes, obesity, chronic obstructive pulmonary disease, low back pain, and arthritis, and they exhibit a trend toward higher mortality compared to controls [33]. Lower cardiovascular fitness fits well into this pattern, as the aforementioned conditions are the result of lower cardiopulmonary fitness, the cause of it, or both [34]. Thus, we recommend that narcolepsy patients perform more physical activity, including a structured exercise program, especially early in the course of the disease. 4.3. Study limitations There are some limitations to the present study, most notably the choice of the control group, which was derived from patients attending preventive programs. These patients, who care about their health, could be more fit and healthy. Nevertheless, the control group matches the cardiovascular fitness national norm derived from the general population. There is also a potential bias in patient selection. Although we invited all patients to participate in this study, some patients refused for various reasons such as lack of time, difficulties with transportation, motivation, or anxiety. The present narcolepsy sample may be healthier than the overall narcolepsy population, and we may speculate that the remaining subjects have even worse cardiopulmonary fitness. Modafinil use prolongs endurance exercise time and reduces the perception of effort in healthy young volunteers [35]. The effect of stimulants on cardiovascular function is still controversial. In healthy subjects, modafinil increases HR and BP [36]; nevertheless, in patients with narcolepsy, such deleterious cardiovascular effects have not been observed [37]. Although the use of stimulants may have influenced the results of cardiopulmonary fitness, their use is the state-of the art treatment, and the results show a treated population of patients with narcolepsy on stable medication. 4.4. Conclusion Cardiopulmonary fitness in NC and NwoC is inversely related to the degree of sleepiness and cataplexy frequency. The explanation is most likely multifactorial. Because cardiopulmonary fitness is the
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single most important risk factor for cardiovascular prognosis, we recommend its determination also in narcolepsy patients as part of their initial examination. Furthermore, long-term interventional studies with structured exercise-based programs in narcolepsy patients are needed to verify this generally valid approach. Acknowledgements The study was supported by a grant from the Ministry of Health of the Czech Republic NT 13238-4/2012. Conflict of interest The authors declare that they have no conflicts of interest. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2017.02.017. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.sleep.2017.02.017. References [1] American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. [2] Burgess CR, Scammell TE. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci 2012;32:12305e11. [3] Dodel R, Peter H, Spottke A, et al. Health-related quality of life in patients with narcolepsy. Sleep Med 2007;8:733e41. [4] Blair SN, Kohl 3rd HW, Paffenbarger Jr RS, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262: 2395e401. [5] Balady GJ, Arena R, Sietsema K, et al. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010;122:191e225. [6] Droogleever Fortuyn HA, Fronczek R, Smitshoek M, et al. Severe fatigue in narcolepsy with cataplexy. J Sleep Res 2012;21:163e9. [7] Iber C. The AASM manual for the scoring of sleep and associated events. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007. [8] Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28:113e21. [9] Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540e5. k Z. Mean values of various indices of physical fitness in [10] Selinger V, Bart une the investigation of Czechoslovak population aged 12e55 years. Prague, Czech Republic: Galen; 1976. aspekty pohybove aktivity. Pra[11] Ma cek M, Radvanský J. Fyziologie a klinicke n; 2011. gue, Czech Republic: Gale [12] Tudor-Locke C, Craig CL, Brown WJ, et al. How many steps/day are enough? For adults. Int J Behav Nutr Phys Act 2011;8:79. [13] McArdle WD, Katch FI, Katch VL, editors. Exercise physiology. 7st ed. Baltimore: Lippincott Williams and Wilkins; 2010. [14] Pizza F, Moghadam KK, Vandi S, et al. Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin. J Sleep Res 2013;22: 32e40. [15] Mochizuki T, Crocker A, McCormack S, et al. Behavioral state instability in orexin knock-out mice. J Neurosci 2004;24:6291e300. [16] Shneerson J. Narcolepsy and mental health. In: Goswami M, Pandi-Perumal S, Thorpy M, editors. Narcolepsy: a clinical guide. New York: Springer; 2010. p. 239e47. [17] Kapella MC, Berger BE, Vern BA, et al. Health-related stigma as a determinant of functioning in young adults with narcolepsy. Plos One 2015;10:e0122478. [18] Broughton R, Ghanem Q, Hishikawa Y, et al. Life effects of narcolepsy: relationships to geographic origin (North American, Asian or European) and to other patient and illness variables. Can J Neurol Sci 1983;10:100e4. [19] Daniels E, King MA, Smith IE, et al. Health-related quality of life in narcolepsy. J Sleep Res 2001;10:75e81. [20] Teixeira VG, Faccenda JF, Douglas NJ. Functional status in patients with narcolepsy. Sleep Med 2004;5:477e83. [21] Bruck D, Kennedy GA, Cooper A, et al. Diurnal actigraphy and stimulant efficacy in narcolepsy. Hum Psychopharmacol 2005;20:105e13.
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[30] Vignatelli L, D'Alessandro R, Mosconi P, et al. Health-related quality of life in Italian patients with narcolepsy: the SF-36 Health Survey. Sleep Med 2004;5: 467e75. [31] Ervik S, Abdelnoor M, Heier MS, et al. Health-related quality of life in narcolepsy. Acta Neurol Scand 2006;114:198e204. [32] Dauvilliers Y, Gosselin A, Paquet J, et al. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 2004;62:46e50. [33] Jennum P, Ibsen R, Knudsen S, et al. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep 2013;36:835e40. [34] Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. Philadelphia: Lippincottt Williams and Wilkins; 2012. [35] Jacobs I, Bell DG. Effects of acute modafinil ingestion on exercise time to exhaustion. Med Sci Sports Exerc 2004;36:1078e82. [36] Taneja I, Diedrich A, Black BK, et al. Modafinil elicits sympathomedullary activation. Hypertension 2005;45:612e8. [37] Roth T, Schwartz JRL, Hirshkowitz M, et al. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007;3: 595e602.
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Original Article
Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes b, Son a Nevsímalova b, Martin Matoulek a, Vladimír Tuka a, Magdalena Fialova b, * Karel Sonka a Centre of Cardiovascular Rehabilitation, Third Department of Medicine e Department of Endocrinology and Metabolism of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic b Department of Neurology and Centre of Clinical Neurosciences of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 December 2015 Received in revised form 17 November 2016 Accepted 16 February 2017 Available online 11 March 2017
Objective: Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. Patients and methods: The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. Results: In narcolepsy patients, maximal oxygen uptake (VO2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p ¼ 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO2peak%) and to a standard deviation (VO2peakSD) of 1.08 ± 1.63 mL/kg/min of the population norm. VO2peak depended primarily on gender (p ¼ 0.007) and on sleepiness (p ¼ 0.046). VO2peak% depended on sleepiness (p ¼ 0.028) and on age (p ¼ 0.039). VO2peakSD depended on the number of cataplexy episodes per month (p ¼ 0.015) and on age (p ¼ 0.030). Conclusions: Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency. © 2017 Elsevier B.V. All rights reserved.
Keywords: Exercise stress test Cardiopulmonary fitness Narcolepsy with cataplexy Narcolepsy without cataplexy Influence of disease severity
1. Introduction Narcolepsy is a chronic neurological disease that is characterized by excessive daytime sleepiness and is divided into narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwoC), due to differing etiologies [1]. NC occurs due to the loss of hypocretin (orexin) neurons in the lateral hypothalamus [2]. In addition to sleep and wakefulness regulation, hypocretin plays an important role in food intake regulation and metabolism. The etiology of NwoC is not well understood, and NwoC is not characterized by hypocretin deficiency in the cerebrospinal fluid.
* Corresponding author. Department of Neurology, First Faculty of Medicine, 30, Prague 2, 128 08, Charles University and General University Hospital, Katerinska Czech Republic. Fax: þ420 224 922 678. E-mail address: [email protected] (K. Sonka). http://dx.doi.org/10.1016/j.sleep.2017.02.017 1389-9457/© 2017 Elsevier B.V. All rights reserved.
Patients with narcolepsy have a lower quality of life compared to other neurological patients. On the Short Form36 questionnaire, the dimensions “physical functioning,” “vitality,” and “general health perception” have been found to be the main domains of health-related decreased quality of life [3]. Exercise tolerance is the strongest prognostic marker of all-cause mortality in the general population [4] and in different chronic diseases, for example, obesity, coronary artery disease, heart failure, and cancer [5]. Exercise tolerance depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy are reported to need more sleep during the daytime and are more fatigued than controls [6]; thus we may speculate that the main determinants of cardiopulmonary fitness in NC and NwoC are due to sleepiness and potentially to cataplexy episodes preventing patients from engaging in regular physical activity. The aim of the present study was to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness.
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2. Methods 2.1. Study population A total of 56 patients aged 18e65 years diagnosed with NC and NwoC, who were indicated for an exercise stress test before the initiation of an exercise program, were included in the present study (years 2013e2015). The age- and gender-matched control group was recruited from among participants of a preventive program for the general population to whom an exercise stress test was offered. All patients gave informed consent to participation in the study. The study was approved by the local ethical committee VFN), and was conducted in accordance with the (40/11 IGA MZCR Declaration of Helsinki. Of the 56 subjects who agreed to participate in the study, 42 patients completed the cardiopulmonary exercise stress test (CPX). One patient had difficulty breathing through the mouthpiece and did not want to reschedule the test with a mask. Thirteen patients did not attend the scheduled CPX and thus were not included. Of the 42 patients who completed the study, eight patients (19%) reported engaging in recreational sports. Five patients had arterial hypertension on monopharmacotherapy. One patient in the study population was treated with a b-blocker, another patient was treated with a statin, and two other patients were treated with a calcium channel blocker. Sixteen patients (38%) were current smokers and four patients (10%) were former smokers. There were no other diagnoses that could potentially affect the results of the CPX. Characteristics of the study population are summarized in Table 1, and the tests performed at narcolepsy diagnosis are summarized in Table 2. All patients were previously diagnosed at our institution, and only those patients with an unambiguous diagnosis were invited to participate. All patients were diagnosed according to the International Sleep Disorders Classification, second edition [1]. In all patients, night polysomnography (8 h) and the 5-nap multiple sleep latency test (MSLT) were performed without any concurrent treatment that could influence sleep or cataplexy. Polysomnography was performed according to the American Academy of Sleep Medicine (AASM) manual for the scoring of sleep and associated events [7] and the MSLT according to AASM rules [8]. Results concerning sleep-related breathing disorders and periodic limb movements in sleep (PLMS) were retrieved from the diagnostic night polysomnography data to provide information about other sleep disturbances. Obstructive sleep apnea (OSA) was diagnosed according to polysomnography (PSG) criteria (apnea/ hypopnea index 5). None of the patients fulfilled the diagnostic criteria for central sleep apnea [1]. Subjects were considered to have PLMS when the number of period leg movements per 1 h was 15 [7]. The mean latency between polysomnography and MSLT and the exercise stress test was 3.6 ± 4 years; however, information about general health status and pharmacological treatment was obtained at the date of the examination. The following information
was selected and processed from the clinical records of all patients: age at data collection, age at symptom onset, body height and weight, Epworth Sleepiness Scale (ESS) score [9], cataplexy episode frequency per month (subjectively assessed), sleep latency during MSLT, sleep efficacy during night polysomnography, rapid eye movement (REM) sleep latency during polysomnography, percentage of slow-wave sleep during night polysomnography, and percentage of REM sleep during night polysomnography. Treatment with stimulants (modafinil and methylphenidate), antidepressants (selective serotonin reuptake inhibitors, venlafaxine, clomipramine, and tianeptine) and sodium oxybate at the time of the exercise test was as summarized in Table 2. 2.2. Cardiopulmonary exercise stress test The CPX were carried out on a cycle ergometer (Ergoline e-Bike, GE Medical Systems, Milwaukee, WI, USA) at the same time, in the early afternoon. The work rate was corrected for body weight. We used a combined protocol with two consecutive 3-min steps, followed by a ramped increase in work intensity. The intensity of the first step was set to correspond to 0.5 Watt/kg (ie, 2.3 metabolic equivalents [METs]), increasing to 1.0 Watt/kg (ie, 4.7 METs) during the second step. Thereafter, a ramped increase in work intensity followed, consisting of 5 Watts/10 s, ie, 30 Watts/min, irrespective of body weight. Blood pressure (BP) measurements were performed by an experienced nurse at the beginning of the third minute of each workload, and at each odd minute during the ramped increase. BP was measured manually by a standard sphygmomanometer using the auscultatory method. Systolic BP (SBP) was recorded at the appearance of the Korotkoff phase I sound, and diastolic BP (DBP) at the disappearance or muffling of the Korotkoff sounds (phase IV or V); preference was at the complete disappearance of the Korotkoff sound, and in the case of uncertainty, diastolic pressure was not noted. Heart rate (HR) in beats per minute (bpm) was measured from the electrocardiogram (ECG) recording by Cardiosoft v6.51 (GE Medical Systems, Milwaukee, WI, USA). Analysis of expired gas was performed breath-by-breath using a Vmax Spectra 29s Cardiopulmonary Exercise Testing Instrument (SensorMedics Corporation, Yorba Linda, Canada). Flow and sensor calibration was performed before each test according to the device manual. The respiratory exchange ratio (RER; VCO2/VO2) and metabolic equivalent of tasks (METs; VO2/basal oxygen demand [3.5 mL/kg/min]) were calculated from the measured variables. Markers of cardiopulmonary fitness included VO2peak (mean from the last 30 s of the exercise test), expressed in mL/kg/min, as a percentage of the national norm (VO2peak%), as well as the number of standard deviations (SD) from the national norm (VO2peakSD). These data were derived from the specific national data from the International Biological Program [10], as it is widely used in reporting fitness data, in which less than 85% and less than one SD are considered abnormal [11].
Table 1 Characteristics of study population.
No. Age (y) Gender (male/female) Weight (kg) Height (cm) BMI
All narcolepsy
NC
NwoC
Control
42 34.9 ± 10.0 16/26 88.0 ± 53.0 171.8 ± 9.1 29.9 ± 5.7
32 35.0 ± 10.0 12/20 89.5 ± 15.3 171.4 ± 9.6 30.6 ± 5.6
10 34.6 ± 10.6 4/6 83.4 ± 20.9 173.0 ± 8.0 27.6 ± 5.7
36 35.3 ± 10.2 15/21 85.6 ± 20.3 174.3 ± 9.7 28.1 ± 6.2
BMI, body mass index; NC, narcolepsy patients; NwoC, narcolepsy patients without cataplexy.
Control vs all narcolepsy
NC vs NwoC
NS NS NS NS NS
NS NS NS NS NS
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Table 2 Characteristics of patients with narcolepsy.
No. Age at disease onset (y) Duration of the disease (y) HLA DQB1*06:02 positivity/total number of subjects with available HLA typing Cataplexy (No./month) No. on stimulants No. on modafinil Mean dose of modafinil (mg) No. on methylphenidate Doses of methylphenidate (mg) No. on antidepressants No. on sodium oxybate Doses of oxybate (g) ESS MSLT, sleep latency (min) MSLT, No. of SOREMp PSG, sleep latency (min) PSG, sleep efficiency (%) PSG REM, sleep latency (min) PSG, REM duration (%) PSG, N3 duration (%) No. of patients diagnosed with OSA AHI No. of patients diagnosed with PLMS PLMI
All
NC
NwoC
NC vs NwoC
42 19.1 ± 9.0 15.3 ± 10.1 30/39
32 18.3 ± 7.8 16.0 ± 10.1 26/29
10 21.7 ± 12.2 13.1 ± 10.2 4/10
NS NS
9.2 ± 17.0 34 (81%) 30 (71%) 208 ± 66 4 (10%)
12.0 ± 18.7 26 (81%) 23 (72%) 209 ± 72 3 (10%) 10 mg; 10 mg; 40 mg 15 (47%) 5 (16%) 5 g, 5 g, 6 g, 6 g, 9 g 17.5 ± 3.6 2.4 ± 2.1 3.7 ± 1.1 7.3 ± 10.0 84.8 ± 8.9 31.9 ± 44.9 19.6 ± 6.0 18.4 ± 6.6 6 (19%) 6.5 ± 12.3 11 (34%) 15.4 ± 23.2
0±0 8 (80%) 7 (70%) 207 ± 42 1 (10%) 10 mg 1 (10%) 0 0 15.9 ± 4.5 3.3 ± 1.3 3.2 ± 0.9 8.0 ± 4.5 90.9 ± 4.9 68.2 ± 33.7 21.2 ± 4.5 17.6 ± 7.4 0 2.0 ± 0.9 2 (20%) 13.6 ± 21.7
16 (38%) 5 (12%) 17.1 ± 3.8 2.62 ± 1.93 3.5 ± 1.0 7.4 ± 9.2 86.3 ± 8.5 39.0 ± 44.9 19.9 ± 5.7 18.2 ± 6.6 6 (14%) 5.6 ± 11.1 13 (31%) 15.0 ± 22.6
NS NS NS NS
NS NS NS NS NS NS NS NS NS
AHI, apnea/hypopnea index; ESS, Epworth Sleepiness Scale; HLA, human leukocyte antigen; MSLT, multiple sleep latency test; NC, narcolepsy patients; NwoC, narcolepsy patients without cataplexy; No., number; OSA, obstructive sleep apnea; PLMI, periodic leg movements index (number of periodic leg movements per 1 h of sleep); PLMS, periodic limb movements in sleep; PSG, polysomnography; REM, rapid eye movement; SOREMp, sleep onset REM period.
2.3. Accelerometer use
3.1. Cardiopulmonary exercise stress test
We used an Omron Walking style Pro accelerometer (Omron Healthcare Europe, Hoofddorp, Netherlands) for step count, which has a measurement deviation of ±5%. The patients wore the accelerometers two weeks before CPX to document their usual physical activity. A direct estimate of minimal amounts of moderate-to-vigorous physical activity accumulated in the course of objectively monitored free-living behavior corresponds to 7000e8000 steps per day [12].
Data from the CPX are reported in Table 3. VO2peak was lower in narcoleptic patients than in controls (30.1 ± 7.5 mL/kg/min vs 36.0 ± 7.8 mL/kg/min; p ¼ 0.001), which corresponds to 86.4% ± 20.0% (vs 101.3% ± 15.4% in controls; p ¼ 0.0007) of the Czech population norm (VO2peak%) or a standard deviation (VO2peakSD) of 1.08 ± 1.63 mL/kg/min (vs 0.12 ± 1.27 mL/kg/min in controls; p ¼ 0.007) from the Czech population norm. The narcoleptic patients also achieved statistically nonsignificantly lower peak workloads than control subjects (223 ± 56 Watt vs 246 ± 69 Watt; p ¼ 0.099). The only statistically significant difference between NC and NwoC was HR at a work intensity of 0.5 Watt/ kg (114 ± 13 bpm vs 103 ± 16 bpm, p ¼ 0.037). Compared to NwoC patients, NC patients had lower values of VO2peak% (84.3% ± 18.9% vs 94.9% ± 22.1%; p ¼ 0.227) and VO2peakSD (1.26 ± 1.58 vs 0.37 ± 1.6 mL/kg/min; p ¼ 0.143), although the difference was not significant.
2.4. Statistical analysis All calculations were performed in SPSS v13.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± SD, and range was reported where appropriate. Comparison between the narcolepsy and control groups was performed with the Student t test. Comparison between the NC and NwoC groups was performed with the nonparametric ManneWhitney test. The Spearman correlation coefficient was used in evaluation between independent and dependent variables. Peak work rate indexed by body weight, VO2peak, and VO2peak% were chosen as dependent variables a priori. Linear regression with multivariate models was then applied with stepwise variable selection. The level of significance was set at p < 0.05. 3. Results Treatment for sleepiness and cataplexy at the time of the exercise stress test is outlined in Table 2. We collected data on the number of daily steps from 34 patients (26 NC and eight NwoC). The mean number of steps per day was 6346 ± 2026 in all patients, 6533 ± 1988 in NC, and 5739 ± 2163 NwoC (difference nonsignificant).
3.2. Linear regression analysis Spearman correlation coefficients were calculated to select appropriate independent variables for the stepwise linear regression analysis; the results of the analysis are summarized separately for NC and NwoC in Table 4 of the Supplementary materials. The number of cataplexy episodes per month, polysomnography-sleep efficiency, gender (male ¼ 1, female ¼ 2), age, body mass index (BMI), and resting HR were chosen as independent variables. The linear regression analysis showed that VO2peak depended primarily on gender (p ¼ 0.007) and on ESS (p ¼ 0.046). The regression equation for VO2peak was as follows:
VO2peak ¼51;7757;244Gender0;606ESS ½Gender : Male ¼ 1;Female ¼ 2
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Table 3 Cardiopulmonary exercise stress test data.
Narcolepsy group
Control group
SBP (mm Hg) DBP (mm Hg) HR (bpm) VO2 (mL/kg/min) SBP (mm Hg) DBP (mm Hg) HR (bpm) VO2 (mL/kg/min)
Rest
0.5 W/kg
1.0 W/kg
Peak
3-min Recovery
123 ± 15 80 ± 9 89 ± 14 N/A 127 ± 17 80 ± 10 89 ± 17 N/A
130 ± 17 81 ± 10 111 ± 15 12.3 ± 1.4 138 ± 22* 81 ± 10 110 ± 12 12.6 ± 1.1
152 ± 23 85 ± 10 134 ± 17 18.9 ± 1.7 157 ± 28 84 ± 10 132 ± 14 20.2 ± 1.5
173 ± 26 91 ± 16 176 ± 13 30.1 ± 7.5 183 ± 32 92 ± 10 175 ± 16 36.0 ± 7.8**
139 ± 20 74 ± 10 121 ± 16 N/A 146 ± 22 75 ± 11 124 ± 13 N/A
DBP, diastolic blood pressure; HR, heart rate; METs, metabolic equivalent of task; N/A, not applicable; RER, respiratory exchange ratio; RPE, rating of perceived exertion according to Borg; SBP, systolic blood pressure; VO2, oxygen consumption. *p < 0.05; **p < 0.01; ***p < 0.001.
VO2peak% depended on ESS (p ¼ 0.028) and on age (p ¼ 0.039). The regression equation for VO2peak% was as follows:
VO2peak % ¼ 89; 747 1; 813 ESS þ 0; 760 age: VO2peakSD depended on the number of cataplexy episodes per month (CAT) (p ¼ 0.015) and on age (p ¼ 0.030). The regression equation for VO2peakSD was as follows:
VO2peak SD ¼ 2; 993 0; 034 CAT þ 0; 063 age: 3.3. Differences between NC and NwoC The NC and NwoC groups differed only in SBP before the CPX (125 ± 15 mm Hg vs 113 ± 14 mm Hg, p ¼ 0.032) and HR during the first exercise stage corresponding to light exercise of 0.5 Watt/kg (114 ± 13 bpm vs 103 ± 16 bpm; p ¼ 0.037). No other significant differences between the two groups were detected. 4. Discussion This is the first study to provide data on cardiopulmonary fitness in patients with narcolepsy. The main findings of the present study are as follows: (1) cardiopulmonary fitness is inversely related to the degree of sleepiness in NC and NwoC and to the number of cataplexy attacks per month in NC; (2) patients with narcolepsy have lower cardiopulmonary fitness compared to the general population; and (3) with increasing age, cardiopulmonary fitness in narcolepsy patients approaches that of general population. 4.1. Lower cardiopulmonary fitness The training effect of exercise is dose dependent; less opportunity to be physically active (including physical activity such as walking, household work, etc) results in lower muscle recruitment and thus through a lower training effect to lower exercise tolerance [13]. In our study population, sleepiness was one of the variables that determined cardiopulmonary fitness. There are several explanations for a lower opportunity to perform physical exercise and to participate in leisure activities combined with sports, including time constraints due to sleepiness, social isolation, and BMI. All of these potential explanations may be applied not only on generally to lower cardiopulmonary fitness in NC and NwoC but also have a negative correlation with the intensity of sleepiness and the frequency of cataplexy episodes. Patients with NC and NwoC sleep more than controls during the daytime, especially during lower sleep-propensity zones (morning and late afternoon) [14], and the majority of patients with narcolepsy experience severe fatigue, which is different from daytime
sleepiness and which results in severe functional impairment [6]. This is in agreement with the model of orexin knock-out (KO) mice that have less spontaneous activity compared to wild-type mice [15]. Similarly, patients with narcolepsy experience more social isolation, as they fear falling asleep or having cataplexy episodes during moments of excitement. This also affects common collective leisure time activities, including sports. Anxiety and depression are frequent comorbidities in narcolepsy [16]. Anxiety and depression as well as health-related stigmata contribute to social isolation [17] and thus to nonparticipation in leisure time physical activity. There is evidence that patients do have limited participation in sport activities. Broughton et al. reported that patients with narcolepsy reported more problems in performing recreational and leisure-time activities compared to controls [18]. Daniels et al. found that 39.7% of British adult narcoleptics reported difficulties with playing sports due to narcolepsy [19]. In addition, Texeira et al. reported that 48% of patients with narcolepsy complained about difficulties playing sports [20]. The explanation of lower cardiopulmonary fitness by reduced daily physical activity in narcolepsy is supported by our data, showing a low average number of steps performed per day. These are below the minimal normative data from objectively monitored, free-living behavioral step count [12]. Similarly, reduced spontaneous activity in narcolepsy, even with modafinil treatment, has been recorded by actigraphy [21]. NC is due to a hypocretin (orexin) deficit [2]. In addition to sleep and wakefulness regulation, hypocretin plays an important role in food intake regulation and metabolism. Compared to healthy controls and NwoC patients, patients with NC have higher BMI, and the proportion of patients with obesity is higher in NC than in NwoC patients [22]. Chabas et al. reported that NC patients had a lower basal metabolism than controls and, surprisingly, that overweight patients ate half as much as others [23]. The behavioral explanations of lower cardiopulmonary fitness are in accordance with the murine orexin KO model. The contribution of orexin signaling to physical activity has been demonstrated in rodents [24]. The orexin KO mice initiated running as often as wild-type mice and ran at normal speed. Nevertheless, the total amount of running was 42% less, with shorter bouts. Of the running bouts, 35% were succeeded by cataplexy episodes or a quick transition to sleep. Orexin KO mice have short sleep latencies and rapid transitions to cataplexy episodes after running, which suggests that sleepiness and imminent cataplexy episodes may contribute behaviorally to their short running bouts and lower amount of time spent running during the day [25]. We observed increased sleepiness in our NC and NwoC patients, and they also took approximately 35% fewer steps per day than the 10,000 steps that a healthy nonsedentary adult takes [12]. These factors suggest a similar pathophysiological role of orexin deficiency in the murine model as well as in humans.
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4.2. Effect of age Narcolepsy is a chronic, lifelong disease that is believed to have a stable course; however, longitudinal studies are scarce [26]. It seems that NC is not a stable phenotype, especially in children, displaying characteristic evolution with an abrupt onset followed by partial improvement over time [27]. The onset of the disease is usually marked by weight gain, especially in childhood [28]. Older patients perceive the symptoms of narcolepsy as milder compared to their younger age [29]. Quality of life in narcolepsy patients also improves with the duration of symptoms [3,26,30], especially vitality [31]. This age-related improvement in narcolepsy symptoms has also been documented by a progressive decrease in the number of SOREMp with age and a progressive increase in mean sleep latency on the MSLT as a function of age [32]. Both the symptoms of the disease, which may reduce habitual physical activity, and the metabolic disturbances associated with narcolepsy are greater at the beginning of the disease and thus affect younger patients more. Cardiopulmonary fitness declines with age [12]; thus otherwise healthy senior patients with narcolepsy are closer to their age-matched counterparts, where the difference in cardiopulmonary fitness is not so pronounced as in younger patients. Narcolepsy is associated with increased morbidity and a trend toward higher mortality. Data from an extensive Danish National Patient Registry show that patients with narcolepsy have a higher prevalence of diabetes, obesity, chronic obstructive pulmonary disease, low back pain, and arthritis, and they exhibit a trend toward higher mortality compared to controls [33]. Lower cardiovascular fitness fits well into this pattern, as the aforementioned conditions are the result of lower cardiopulmonary fitness, the cause of it, or both [34]. Thus, we recommend that narcolepsy patients perform more physical activity, including a structured exercise program, especially early in the course of the disease. 4.3. Study limitations There are some limitations to the present study, most notably the choice of the control group, which was derived from patients attending preventive programs. These patients, who care about their health, could be more fit and healthy. Nevertheless, the control group matches the cardiovascular fitness national norm derived from the general population. There is also a potential bias in patient selection. Although we invited all patients to participate in this study, some patients refused for various reasons such as lack of time, difficulties with transportation, motivation, or anxiety. The present narcolepsy sample may be healthier than the overall narcolepsy population, and we may speculate that the remaining subjects have even worse cardiopulmonary fitness. Modafinil use prolongs endurance exercise time and reduces the perception of effort in healthy young volunteers [35]. The effect of stimulants on cardiovascular function is still controversial. In healthy subjects, modafinil increases HR and BP [36]; nevertheless, in patients with narcolepsy, such deleterious cardiovascular effects have not been observed [37]. Although the use of stimulants may have influenced the results of cardiopulmonary fitness, their use is the state-of the art treatment, and the results show a treated population of patients with narcolepsy on stable medication. 4.4. Conclusion Cardiopulmonary fitness in NC and NwoC is inversely related to the degree of sleepiness and cataplexy frequency. The explanation is most likely multifactorial. Because cardiopulmonary fitness is the
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single most important risk factor for cardiovascular prognosis, we recommend its determination also in narcolepsy patients as part of their initial examination. Furthermore, long-term interventional studies with structured exercise-based programs in narcolepsy patients are needed to verify this generally valid approach. Acknowledgements The study was supported by a grant from the Ministry of Health of the Czech Republic NT 13238-4/2012. Conflict of interest The authors declare that they have no conflicts of interest. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2017.02.017. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.sleep.2017.02.017. References [1] American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. [2] Burgess CR, Scammell TE. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci 2012;32:12305e11. [3] Dodel R, Peter H, Spottke A, et al. Health-related quality of life in patients with narcolepsy. Sleep Med 2007;8:733e41. [4] Blair SN, Kohl 3rd HW, Paffenbarger Jr RS, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262: 2395e401. [5] Balady GJ, Arena R, Sietsema K, et al. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010;122:191e225. [6] Droogleever Fortuyn HA, Fronczek R, Smitshoek M, et al. Severe fatigue in narcolepsy with cataplexy. J Sleep Res 2012;21:163e9. [7] Iber C. The AASM manual for the scoring of sleep and associated events. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007. [8] Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28:113e21. [9] Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540e5. k Z. Mean values of various indices of physical fitness in [10] Selinger V, Bart une the investigation of Czechoslovak population aged 12e55 years. Prague, Czech Republic: Galen; 1976. aspekty pohybove aktivity. Pra[11] Ma cek M, Radvanský J. Fyziologie a klinicke n; 2011. gue, Czech Republic: Gale [12] Tudor-Locke C, Craig CL, Brown WJ, et al. How many steps/day are enough? For adults. Int J Behav Nutr Phys Act 2011;8:79. [13] McArdle WD, Katch FI, Katch VL, editors. Exercise physiology. 7st ed. Baltimore: Lippincott Williams and Wilkins; 2010. [14] Pizza F, Moghadam KK, Vandi S, et al. Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin. J Sleep Res 2013;22: 32e40. [15] Mochizuki T, Crocker A, McCormack S, et al. Behavioral state instability in orexin knock-out mice. J Neurosci 2004;24:6291e300. [16] Shneerson J. Narcolepsy and mental health. In: Goswami M, Pandi-Perumal S, Thorpy M, editors. Narcolepsy: a clinical guide. New York: Springer; 2010. p. 239e47. [17] Kapella MC, Berger BE, Vern BA, et al. Health-related stigma as a determinant of functioning in young adults with narcolepsy. Plos One 2015;10:e0122478. [18] Broughton R, Ghanem Q, Hishikawa Y, et al. Life effects of narcolepsy: relationships to geographic origin (North American, Asian or European) and to other patient and illness variables. Can J Neurol Sci 1983;10:100e4. [19] Daniels E, King MA, Smith IE, et al. Health-related quality of life in narcolepsy. J Sleep Res 2001;10:75e81. [20] Teixeira VG, Faccenda JF, Douglas NJ. Functional status in patients with narcolepsy. Sleep Med 2004;5:477e83. [21] Bruck D, Kennedy GA, Cooper A, et al. Diurnal actigraphy and stimulant efficacy in narcolepsy. Hum Psychopharmacol 2005;20:105e13.
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